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Bone Marrow Failure
Hematopoietic stem cell loss and hematopoi- etic failure in severe aplastic
anemia is driven by macrophages and aberrant podoplanin expression
Amanda McCabe,1* Julianne N.P. Smith,1** Angelica Costello,1 Jackson Maloney,1 Divya Katikaneni1 and Katherine C. MacNamara1
Ferrata Storti Foundation
1Department for Immunology and Microbial Disease, Albany Medical College, NY, USA
Haematologica 2018 Volume 103(9):1451-1461
AM and JNPS contributed equally to this work. *Current address: Boston Children’s Hospital, Division of Hematology/Oncology, Harvard Medical School, Karp Family Research Lab, Boston, MA, USA. **Current address: Case Western Reserve University, Department of Medicine, Wolstein Research Building, Cleveland, OH, USA
ABSTRACT
Severe aplastic anemia (SAA) results from profound hematopoietic stem cell loss. T cells and interferon gamma (IFNγ) have long been associated with SAA, yet the underlying mechanisms driving hematopoietic stem cell loss remain unknown. Using a mouse model of SAA, we demonstrate that IFNγ-dependent hematopoietic stem cell loss required macrophages. IFNγ was necessary for bone marrow macrophage persistence, despite loss of other myeloid cells and hematopoietic stem cells. Depleting macrophages or abrogating IFNγ sig- naling specifically in macrophages did not impair T-cell activation or IFNγ production in the bone marrow but rescued hematopoietic stem cells and reduced mortality. Thus, macrophages are not required for induction of IFNγ in SAA and rather act as sensors of IFNγ. Macrophage depletion rescued thrombocytopenia, increased bone marrow megakaryocytes, preserved platelet-primed stem cells, and increased the platelet-repopulating capacity of transplanted hematopoietic stem cells. In addition to the hematopoietic effects, SAA induced loss of non- hematopoietic stromal populations, including podoplanin-positive stro- mal cells. However, a subset of podoplanin-positive macrophages was increased during disease, and blockade of podoplanin in mice was suffi- cient to rescue disease. Our data further our understanding of disease pathogenesis, demonstrating a novel role for macrophages as sensors of IFNγ, thus illustrating an important role for the microenvironment in the pathogenesis of SAA.
Introduction
Severe aplastic anemia (SAA) is a rare, lethal bone marrow (BM) failure disease that can be inherited or acquired. The most effective treatment for SAA is BM transplantation but disease management also includes immunosuppressive therapy (IST). Not all patients are good transplant candidates, however, and IST responsive- ness varies. Therefore more specific treatments are necessary.1,2
Chemical-induced toxicity, myeloablation, and lymphocyte infusion-based BM destruction have been used to model SAA in mice and define factors critical for ini- tiating disease.1,2 SAA can be acquired as a result of radiation, toxic drug exposure, or infection. Acquired forms are often immune-mediated,3 thus the lymphocyte- infusion model is clinically relevant. Sublethal irradiation and subsequent lympho- cyte or bulk splenocyte transfer elicits pancytopenia and death within 2-3 weeks.4 Importantly, disease progression and IST treatment responses are similar to those in SAA patients.5 T cells promote hematopoietic stem cell (HSC) loss during SAA through a “bystander effect” involving inflammatory cytokines, including IFNγ.6-9 IFNγ negatively regulates HSC function, and it was first observed over thirty years ago that SAA patients show elevated IFNγ levels.10 Despite this knowledge, the
Correspondence:
macnamk@amc.edu
Received: January 30, 2018. Accepted: May 14, 2018. Pre-published: May 17, 2018.
doi:10.3324/haematol.2018.189449
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/9/1451
©2018 Ferrata Storti Foundation
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